Inhibition of Met/HGF receptor and angiogenesis by NK4 leads to suppression of tumor growth and migration in malignant pleural mesothelioma

AbstractMalignant pleural mesothelioma (MPM) is an aggressive neoplasm originating from the pleura. Non-epithelioid (biphasic and sarcomatoid) MPM are particularly resistant to therapy. We investigated the role of the GITR-GITRL pathway in mediating the resistance to therapy. We found that GITR and GITRL expressions were higher in the sarcomatoid cell line (CRL5946) than in non-sarcomatoid cell lines (CRL5915 and CRL5820), and that cisplatin and Cs-137 irradiation increased GITR and GITRL expressions on tumor cells. Transcriptome analysis demonstrated that the GITR-GITRL pathway was promoting tumor growth and inhibiting cell apoptosis. Furthermore, GITR+ and GITRL+ cells demonstrated increased spheroid formation in vitro and in vivo. Using patient derived xenografts (PDXs), we demonstrated that anti-GITR neutralizing antibodies attenuated tumor growth in sarcomatoid PDX mice. Tumor immunostaining demonstrated higher levels of GITR and GITRL expressions in non-epithelioid compared to epithelioid tumors. Among 73 patients uniformly treated with accelerated radiation therapy followed by surgery, the intensity of GITR expression after radiation negatively correlated with survival in non-epithelioid MPM patients. In conclusion, the GITR-GITRL pathway is an important mechanism of autocrine proliferation in sarcomatoid mesothelioma, associated with tumor stemness and resistance to therapy. Blocking the GITR-GITRL pathway could be a new therapeutic target for non-epithelioid mesothelioma.

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TGFα Promotes Chemoresistance of Malignant Pleural Mesothelioma

Cancers ◽

10.3390/cancers12061484 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1484

Author(s):

Bernard Staumont ◽

Majeed Jamakhani ◽

Chrisostome Costa ◽

Fabian Vandermeers ◽

Sathya Neelature Sriramareddy ◽

...

Keyword(s):

Rna Interference ◽

Growth Factor ◽

Tumor Growth ◽

Mouse Models ◽

Differentially Expressed Genes ◽

Malignant Pleural Mesothelioma ◽

Transforming Growth Factor ◽

Therapeutic Option ◽

Differentially Expressed ◽

Pleural Mesothelioma

Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGFα) was associated with resistance to this regimen. The silencing of TGFα by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGFα desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGFα receptor (epidermal growth factor receptor/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGFα expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGFα but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy.

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Therapeutic targeting of polyamines in malignant pleural mesothelioma xenograft models.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20060 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20060-e20060

Author(s):

James C. M. Ho ◽

Sheng Yan ◽

Sze Kwan Lam

Keyword(s):

Adjuvant Therapy ◽

Tumor Growth ◽

Malignant Pleural Mesothelioma ◽

Nude Mice ◽

Pleural Mesothelioma ◽

Term Survival ◽

Early Stage Disease ◽

Therapeutic Setting ◽

Metastatic Setting ◽

Humane Endpoint

e20060 Background: Although the use of asbestos has been restricted, the incidence of malignant pleural mesothelioma (MPM) is still rising. The US FDA approved a combination of pemetrexed with cisplatin for treatment of unresectable MPM. And development of novel adjuvant therapeutic options for resected early-stage disease is also urgently needed. From our preliminary data, ornithine decarboxylase (ODC) is highly expressed in MPM xenografts and clinical tumor samples. Upregulation of ODC increases polyamines production and enhances tumor growth. a-difluoromethylornithine (DFMO) is a specific ODC inhibitor. This study aims to disclose the adjuvant (minimal residual disease setting) and therapeutic (metastatic setting) effects of DFMO in MPM xenografts. Methods: In adjuvant therapy setting, nude mice were fed with DFMO in drinking water 7 days before subcutaneous inoculation of 200,000 tumor cells. In therapeutic setting, 107 corresponding cells were injected subcutaneously into nude mice which were randomized for treatment after established tumor growth. Mice with tumor size > 600mm3 were considered reaching humane endpoint. Spermidine levels, protein expression, cytokines concentration, and apoptosis were investigated by Dot plot, Western blot, ELISA, and TUNEL assay respectively. Results: In adjuvant therapy setting, DFMO suppressed tumor growth and increased median survival in both 211H and H226 xenografts. In H226 xenografts, 43% of treated mice have not yet reached humane endpoint, mimicking long-term survival. Upon DFMO treatment, decrease in spermidine level, increase in nitrotyrosine content, and activation of apoptosis were observed in both xenografts. In addition, increase in nitrosocysteine level, intratumoral IL-6, keratinocyte chemoattractant and TNFα, DNA lesions and inhibition of Akt/mTOR pathway were induced by DFMO in H226 xenografts, which may explain higher potency of DFMO in these xenografts. In therapeutic setting, DFMO also suppressed tumor growth in both xenografts with similar mechanisms. Conclusions: DFMO may have a potential role as adjuvant therapy in MPM especially epithelioid mesothelioma.

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Complement Protein C1q Binds to Hyaluronic Acid in the Malignant Pleural Mesothelioma Microenvironment and Promotes Tumor Growth

Frontiers in Immunology ◽

10.3389/fimmu.2017.01559 ◽

2017 ◽

Vol 8 ◽

Cited By ~ 13

Author(s):

Chiara Agostinis ◽

Romana Vidergar ◽

Beatrice Belmonte ◽

Alessandro Mangogna ◽

Leonardo Amadio ◽

...

Keyword(s):

Hyaluronic Acid ◽

Tumor Growth ◽

Malignant Pleural Mesothelioma ◽

Pleural Mesothelioma ◽

Complement Protein

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P3.03-032 PET/CT for Patients with Very Early Clinical Stage of Malignant Pleural Mesothelioma: When Can PET/CT Detect Tumor Growth of T0/T1a Mesothelioma?

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2016.11.1931 ◽

2017 ◽

Vol 12 (1) ◽

pp. S1364

Author(s):

Yoshiki Negi ◽

Kozo Kuribayashi ◽

Eriko Fujimoto ◽

Yuichi Koda ◽

Shingo Kanemura ◽

...

Keyword(s):

Tumor Growth ◽

Malignant Pleural Mesothelioma ◽

Clinical Stage ◽

Pleural Mesothelioma ◽

Pet Ct ◽

Early Clinical Stage

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Inhibition of Human Malignant Pleural Mesothelioma Growth by Mesenchymal Stromal Cells

Cells ◽

10.3390/cells10061427 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1427

Author(s):

Valentina Coccè ◽

Silvia La Monica ◽

Mara Bonelli ◽

Giulio Alessandri ◽

Roberta Alfieri ◽

...

Keyword(s):

Tumor Growth ◽

Mesenchymal Stromal Cells ◽

Malignant Pleural Mesothelioma ◽

Stromal Cells ◽

Large Scale ◽

Significant Inhibition ◽

G1 Arrest ◽

Pleural Mesothelioma ◽

Scale Production

Background: Malignant Pleural Mesothelioma (MPM) is an aggressive tumor that has a significant incidence related to asbestos exposure with no effective therapy and poor prognosis. The role of mesenchymal stromal cells (MSCs) in cancer is controversial due to their opposite effects on tumor growth and in particular, only a few data are reported on MSCs and MPM. Methods: We investigated the in vitro efficacy of adipose tissue-derived MSCs, their lysates and secretome against different MPM cell lines. After large-scale production of MSCs in a bioreactor, their efficacy was also evaluated on a human MPM xenograft in mice. Results: MSCs, their lysate and secretome inhibited MPM cell proliferation in vitro with S or G0/G1 arrest of the cell cycle, respectively. MSC lysate induced cell death by apoptosis. The efficacy of MSC was confirmed in vivo by a significant inhibition of tumor growth, similar to that produced by systemic administration of paclitaxel. Interestingly, no tumor progression was observed after the last MSC treatment, while tumors started to grow again after stopping chemotherapeutic treatment. Conclusions: These data demonstrated for the first time that MSCs, both through paracrine and cell-to-cell interaction mechanisms, induced a significant inhibition of human mesothelioma growth. Since the prognosis for MPM patients is poor and the options of care are limited to chemotherapy, MSCs could provide a potential new therapeutic approach for this malignancy.

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The Correlations between CXCL12, CXCR4, EAAT1 and GS in Malignant Pleural Mesothelioma, and CXCL12 Regulates Cell Invasion and Migration via CXCR4/EAAT1/GS Pathway

10.20944/preprints202009.0380.v1 ◽

2020 ◽

Author(s):

Shuo Li ◽

Tong Li ◽

Qiang Lin ◽

Debing Shi ◽

Haishi Zheng ◽

...

Keyword(s):

Malignant Pleural Mesothelioma ◽

Cell Invasion ◽

Mrna Level ◽

Migration And Invasion ◽

Pleural Mesothelioma ◽

Mrna Levels ◽

Cxcr4 Antagonist ◽

Invasion And Migration ◽

Normal Tissues ◽

And Migration

Purpose: To elucidate the mechanism of CXCR4/EAAT1/GS pathway in CXCL12 regulating invasion and migration in malignant pleural mesothelioma (MPM). Methods: Immunohistochemistry for CXCL12, CXCR4, EAAT1 and GS stainings and correlation analysis between them were conducted in MPM and normal tissues. Western blot and real-time PCR were performed to examine the CXCR4, EAAT1 and GS expression in H2052 cells. Wound healing and transwell assay were applied to determine the cell migration and invasion. MTT was utilized to assess cell viability. Results: CXCL12, CXCR4, EAAT1 and GS were highly expressed in MPM tissues and correlated with each other. CXCL12 upregulated both in protein and mRNA levels of CXCR4, EAAT1 and GS in H2052 cells. The EAAT1 and GS expression upregulated or not by CXCL12 were decreased by CXCR4 and EAAT1 knockdown. CXCR4 antagonist AMD3100 and EAAT1 antagonist TFB-TBOA also resulted in the same effects as CXCR4 and EAAT1 knockdown, respectively. CXCL12 promoted cell invasion and migration and increased the Matrix metalloproteinase 9 (MMP9) mRNA level. CXCR4 and EAAT1 knockdown suppressed all these functions. Furthermore, CXCL12 promoted H2052 cells growth in nude mice, both AMD3100 and TFB-TBOA inhibited this promotion. Conclusions: CXCL12 regulated the invasion and migration through CXCR4/EAAT1/GS pathway in H2052 cells.

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